In vivo control of diabetogenic T-cells by regulatory CD4 +CD25+ T-cells expressing Foxp3

Abstract

To understand the ability of regulatory T-cells to control diabetes development in clinically relevant situations, we established a new model of accelerated diabetes in young DP-BB rats by transferring purified T-cells from DR-BB rats made acutely diabetic. Transfer of 3, 5, 10, or 23 million pure in vitro-activated T-cells accelerated diabetes onset in >90% of the recipients, with the degree of acceleration being dosage dependent. Cotransfer of unfractionated leukocytes from healthy donors prevented diabetes. Full protection was achieved when protective cells were transferred 3-4 days before diabetogenic cells, whereas transfer 2 days before conferred only partial protection. Protection resided in the CD4+ fraction, as purified CD4+ T-cells prevented the accelerated diabetes. When CD25 + cells were depleted from these cells before they were transferred, their ability to prevent diabetes was impaired. In contrast, two million CD4+CD25+ cells (expressing Foxp3) prevented the accelerated diabetes when transferred both before and simultaneously with the diabetogenic T-cells. In addition, 2 million CD4+CD25+ T-cells prevented spontaneous diabetes, even when given to rats age 42 days, whereas 20 million CD4+CD25- cells (with low Foxp3 expression) were far less effective. We thus demonstrated that CD4 +CD25+ cells exhibit powerful regulatory potential in rat diabetes. © 2005 by the American Diabetes Association.